Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies characterized by dysplastic and ineffective hematopoiesis. MDS bone marrow precursors have a larger cell size, deregulated proliferation and maturation, and accelerated attrition by programmed cell death (List A, et al. N Engl J Med. 2005 352(6):549-57; Span L. F, et al. Leuk Res. 2007 31(12):1659-67; Garcia-Manero G. Am J Hematol. 2014 89(1):97-108). Despite these shared phenotypes, MDS harbor a spectrum of clonal chromosome abnormalities and somatic gene mutations, the latter most commonly involving genes encoding RNA splicing and epigenetic regulatory proteins (Bejar R, et al. J Clin Oncol. 2011 29(5):504-15; Yoshida K, et al. Nature. 2011 478(7367):64-9). How such diverse genetic events initiate a common MDS phenotype is unexplained.
Apoptosis, a non-inflammatory form of programmed cell death, has been implicated in the ineffective hematopoiesis in MDS based upon membrane phosphatidylserine externalization, mitochondrial depolarization, and DNA fragmentation. Nevertheless, the inflammatory cytokine and cellular milieu instead support innate immune activation (Takizawa, H., et al. Blood 2012 119:2991-3002). Inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α, transforming growth factor-β, IL-6 and others are generated in excess in MDS accompanied by marked bone marrow expansion of hematopoietic-inhibitory, myeloid derived suppressor cells (MDSC) driven by the danger associated molecular pattern (DAMP) and Toll-like receptor (TLR)-4 and CD33 ligand, S100A9 (Mundle, S D. et al. Blood 199688:2640-2647; Chen, X. et al. J Clin Invest 2013 123:4595-4611; Vogl, T. et al. Nat Med 2007 13:1042-1049; Ehrchen, J M., et al. J Leukoc Biol 2009 86:557-566). MDS hematopoietic stem and progenitor cells (HSPC) over-express TLRs and their signaling intermediates, whose activation has been implicated in the proliferation of MDS progenitors and the pathogenesis of peripheral blood cytopenias (Maratheftis, C I., et al. Clin Cancer Res 2007 13:1154-1160; Rhyasen, G W. et al. Cancer Cell 2013 24:90-104; Hofmann, W K. et al. Blood 2002 100:3553-3560).
Recent studies have shown that activation of TLRs by select DAMPs can trigger pyroptosis, a novel caspase-1-dependent pro-inflammatory cell death (Brennan, M. A., and Cookson, B. T. Molecular microbiology 2000 38:31-40; Cookson, B. T., and Brennan, M. A. Trends in microbiology 2001 9:113-114; Masters, S. L., et. Al. Immunity 2012 37:1009-1023) that involves the activation of ion gradients, cell swelling and the release of IL-1β and IL-18, intracellular DAMPs and other pro-inflammatory cytokines (Bergsbaken, T., et. al. Nature Reviews Microbiology 2009 7:99-109). Pyroptosis is mediated by the formation of inflammasome complexes, which are cytosolic heptameric oligomers composed of nucleotide-binding domain and leucine-rich repeat pattern recognition receptors (NLRs). The best characterized NLR, NLRP3, undergoes a conformational change in response to DAMP interaction to recruit the adapter protein, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and pro-caspase-1, which in turn cleaves pro-IL-1β & pro-IL-18 to generate their active forms. Inflammasome activation involves NFκB-induced transcriptional priming of inflammasome components, followed by cation channel activation with cell volume expansion and inflammasome component assembly (Bergsbaken, T., et. al. Nature Reviews Microbiology 2009 7:99-109; Brennan, M. A., and Cookson, B. T. Molecular microbiology 2000 38:31-40; Cookson, B. T., and Brennan, M. A. Trends in microbiology 2001 9:113-114; Fantuzzi, G., and Dinarello, C. A. Journal of clinical immunology 1999 19:1-11). Inflammasome assembly is induced by S100A9 homodimers and S100A8/9 heterodimers, which function as alarmins that induce NADPH oxidase to generate reactive oxygen species (ROS), and which extracellularly direct paracrine inflammatory signals (Fantuzzi, G., and Dinarello, C. A. Journal of clinical immunology 1999 19:1-11; Kessel, C., et. al. Clinical immunology 2013 147:229-241; Lim, S. Y., et. al. Journal of leukocyte biology 2009 86:577-587; Simard, J. C., et. al. PloS One 2013 8:e72138).
Accordingly, there is a need for new methods of treatment and methods of diagnosis for myelodysplastic syndromes (MDS).